It is generally known to coat oral dosage forms, e.g. tablets or pellets, which comprise an acid-labile active ingredient, with an enteric coating which, after passing through the stomach, rapidly dissolves in the alkaline medium in the intestine. One example of such acid-labile active ingredients comprises acid-labile proton pump inhibitors (H+/K+-ATPase inhibitors), in particular pyridin-2-ylmethylsulfinyl-1H-benzimidazoles like those disclosed, for example, in EP-A-0 005 129, EP-A-0 166 287, EP-A-0 174 726 and EP-A-0 268 956. Because of their H+/K+-ATPase-inhibiting effect, they are important in the therapy of disorders originating from increased gastric acid secretion. Examples of active ingredients from this group which are already commercially available are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: omeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: lansoprazole) and 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole (INN: rabeprazole).
Because of their great tendency to decompose in a neutral and, in particular, acidic environment, with production also of highly colored decomposition products, it is also necessary in this case for oral preparations to protect active ingredients from the effect of acids. With the very acid-labile pyridin-2-ylmethylsulfinyl-1H-benzimidazoles it is additionally necessary for them to be processed in the tablet core or in pellets in the form of their alkaline salts, for example as sodium salts, or together with alkaline substances. Since substances suitable for enteric coatings are those with free carboxyl groups, the problem arises that the enteric coating is, because of the alkaline medium in the interior, partially or even completely dissolved from inside, and the free carboxyl groups promote decomposition of the active ingredient. It is therefore necessary to provide a sealing intermediate layer (subcoating) between the enteric coating and the alkaline tablet core or pellet. EP-A-0 244 380 proposes that cores which contain the active ingredient together with alkaline compounds or as alkaline salt be coated with at least one layer which is soluble in water or rapidly disintegrates in water and is composed of nonacidic, inert pharmaceutically acceptable substances, before the enteric layer is applied. The intermediate layer or intermediate layers act as pH-buffering zones in which hydrogen ions diffusing in from outside are able to react with the hydroxyl ions diffusing out of the alkaline core. In order to increase the buffer capacity of the intermediate layer, it is proposed to incorporate buffer substances into the intermediate layer(s). By this process it is possible in practice to obtain reasonably stable preparations. However, relatively thick intermediate layers are required in order to avoid the unsightly discolorations which occur even with only slight decomposition. In addition, considerable effort must be invested to avoid traces of moisture during production.
WO96/01623, WO96/01624 and WO96/01625 describe a dosage form for acid-labile H+/K+-ATPase inhibitors where the active ingredient units are compressed together with tablet excipients to give a tablet. The active ingredient units consist of cores which contain the acid-labile H+/K+-APTase inhibitor together with alkaline compounds or as alkaline salt. The cores of the active ingredient units are coated with one or more layers, and at least one layer has enteric properties. The enteric layer must in this case have mechanical characteristics such that the acid resistance of the active ingredient units is not impaired on compression to tablets. WO97/25030 describes the processing of the aforementioned active ingredient units to a multiparticulate (multiple unit) effervescent tablet. In this case too it is necessary for the enteric layer to have mechanical characteristics such that the acid resistance of the active ingredient units is not impaired on compression of the active ingredient units with the other ingredients of the effervescent tablet.
EP 0 548 356 describes a rapidly disintegrating multiparticulate tablet form where the active ingredient is in the form of coated microcrystals or coated microgranules. This rapidly disintegrating tablet form is said to have the advantage that it can be taken by the patient very simply and anywhere, because it can be taken without water. In addition, this form is said to have advantages for patients who have difficulties with swallowing, such as, for example, elderly people and small children. It would be desirable to provide acid-labile active ingredients likewise in such a form. As the aforementioned background art shows, however, the production of dosage forms such as tablets for acid-labile active ingredients, in particular for acid-labile proton pump inhibitors, requires technically complicated processes because it is necessary, for example, to avoid the acid resistance of the active ingredient units being impaired on compression of the active ingredient with the tablet excipients.